N-aminoalkyldibenzothiophenecarboxamides new dopamine receptor subtype specific ligands

ABSTRACT

Disclosed are compounds of the formula:                    
     or the pharmaceutically acceptable acid addition salts thereof, wherein: 
     R 1 , R 2 , R 3 , R 4  are the same or different and represent hydrogen, C 1 -C 6  alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkoxy, —O 2 CR′, —NHCOR′, —COR′, —SO m R′, where R′ is C 1 -C 6  alkyl and wherein m is 0, 1 or 2; or 
     R 1 , R 2 , R 3 , R 4  independently represent —CONR′R″, or —NR′R″ where R′ and R″ independently represent hydrogen or C 1 -C 6  alkyl; 
     R 5  is hydrogen or C 1 -C 6  alkyl; and 
     R represents an aminoalkyl group, which compounds are useful in the treatment of affective disorders such as schizophrenia, depression, Alzheimer&#39;s disease, movement disorders such as Parkinsonism and dystonia, and other disorders which respond to dopaminergic blockade such as substance abuse and obsessive compulsive disorders. Further, compounds of this invention may be useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.

This is a continuation of application Ser. No. 09/368,542 filed Aug. 5,1999 now U.S. Pat. No. 6,040,459 which is a continuation of Ser. No.09/088,331, filed Jun. 1, 1998; now U.S. Pat. No. 5,929,246 which is acontinuation of Ser. No. 08/619,429, filed Mar. 21, 1996 now U.S. Pat.No. 5,763,609.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to dibenzothiophenecarboxamide derivatives whichselectively bind to brain dopamine receptor subtypes. More specifically,it relates to N-aminoalkyldibenzothiophenecarboxamindes and topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in the treatment or prevention ofvarious neuropsychochological disorders such as schizophrenia and othercentral nervous system diseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the drain. The dopamine D₃ receptor subtype has recently beenidentified (Sokoloff et al., Nature, 347: 146 (1990). Its uniquelocalization in limbic brain areas and its differential recognition ofvarious antipsychotics suggest that the D₃ receptor may play a majorrole in the etiology of schizophrenia. Selective D₃ antagonists may beeffective antipsychotics free from the neurological side effectsdisplayed by conventional neuroleptics. Compounds of the presentinvention demonstrate high affinity and selectivity in binding to the D₃receptor subtype. They may be of potential use in treatment ofschizophrenia, psychotic depression and mania. Other dopamine-mediateddiseases such as Parkinsonism and tardive dyskinesias may also betreated directly or indirectly by modulation of D₃ receptors.

U.S. Pat. No. 5,395,835 discloses N-aminoalkyl-2-napthalamides whichhave affinity at dopamine D₃ receptors. The compounds the presentinvention differ significantly from this prior art in that they possessa dipenzothiophenecarboxamide substructure.

Murray et al., in Bioorg. Med. Chem. Let., 5: 219 (1995), describes4-carboxamido-biphenyls said to have affinity for dopamine D₃ receptors.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine receptor subtypes. Thus, the invention provides compounds ofgeneral Formula I useful in the treatment and/or prevention of variousneuropsychological disorders. The invention also provides pharmaceuticalcompositions comprising compounds of Formula 1.

The invention further relates to the use of such compounds andcompositions in the treatment of affective disorders such asschizophrenia, depression, Alzheimer's disease and certain movementdisorders such as Parkinsonism and dystonia. Compounds of this inventionare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents. Further, the compoundsof the present invention are useful for the treatment of other disorderswhich respond to dopaminergic blockade such as substance abuse andobsessive compulsive disorder.

Since dopamine D₃ receptors are concentrated in the limbic system(Taubes, Science 265 (1994) 1034) which controls cognition and emotion,compounds which interact with these receptors also have utility in thetreatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders involving memory impairment or attention deficit disorders canalso be treated with the compounds of this invention that interactspecifically with the dopamine D₃ receptor subtype.

Furthermore, compounds of this invention may be useful in treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₃receptors which selectively exist in limbic area known to controlemotion and cognitive functions. The compounds of the present inventionare also useful for the treatment of other disorders which respond todopaminergic blockade such as substance abuse (Caine and Koob, Science,260: 1814 (1993)) and obsessive compulsive disorder (Goodman et al.,Clin. Psychopharmacol., 7: 35 (1992)). The interaction of the compoundsof the invention with dopamine receptor subtypes is demonstrated below.This interaction results in the pharmacological activities of thesecompounds.

Accordingly, a broad embodiment of the invention is directed to acompound of Formula I:

or the pharmaceutically acceptable acid addition salts thereof, wherein:

R₁, R₂, R₃, R₄ are the same or different and represent hydrogen, C₁-C₆alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl,trifluoromethoxy, C₁-C₆ alkoxy, —O₂CR′, —NHCOR′, —COR′, —SO_(m)R′, whereR′ is C₁-C₆ alkyl and wherein m is 0, 1 or 2; or

R₁, R₂, R₃, R₄ independently represent —CONR′R″, or —NR′R″ where R′ andR″ independently represent hydrogen or C₁-C₆ alkyl;

R₅ is hydrogen or C₁-C₆ alkyl; and

R represents an aminoalkyl group.

Thus, the invention relates to the use of compounds of formula I in thetreatment and/or prevention of neuropsychochological disordersincluding, but not limited to, schizophrenia, mania, dementia,depression, anxiety, compulsive behavior, substance abuse, memoryimpairment, cognitive deficits, Parkinson-like motor disorders andmotion disorders related to the use of neuroleptic agents.

DETAILED DESCRIPTION OF THE INVENTION

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IA:

wherein:

R₁, R₂, R₃, R₄, R₅ are as defined above; and

R represents an aminoalkyl group of the formula

where

A represents an alkylene group of 2 to 6 carbon atoms optionallysubstituted with one or more alkyl groups having from 1 to 4 carbonatoms;

Z is N or C;

R₆ and R₇ are the same or different and represent hydrogen or C₁-C₆alkyl; or

R₆ and R₇ together with the the 6-membered ring to which they areattached form a 5 to 8-membered ring; and

W is phenyl, naphthyl, 1-(5,6,7,8-tetrahydro)naphthyl or4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quinolinyl, isoquinolinyl,benzofuranyl, benzothienyl; each of which is optionally substituted withup to three groups independently selected from halogen, C₁-C₆ alkyl,C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino,cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula IA include those where R₁-R₄ are hydrogenand A is alkylene of 3-5 carbon atoms.

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IB:

wherein:

R₁, R₂, R₃, R₄, and R₅ are as defined above;

R₆ and R₇ are the same or different and represent hydrogen or C₁-C₆alkyl; or

R₆ and R₇ together with the the 6-membered ring to which they areattached form a 5 to 8-membered rings; and

A, Z and W are as defined above.

The present invention further encompasses compounds of Formula II:

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇, A, and W are as defined above.

Preferred compounds of formula II are those where R₁-R₅ are hydrogen; Ais C₃-C₅ alkylene; and W is quinolinyl, naphthyl or a phenyl groupoptionally substituted with up to three groups independently selectedfrom halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino,monoalkylamino, dialkylamino, cyano, nitro, trifluoromethoxy. Morepreferred compounds of formula II are those where R₁-R₅ are hydrogen; Ais C₃-C₅ alkylene; and W is 8-quinolinyl, naphthyl or a phenyl groupoptionally substituted with up to two groups in the 2 and/or 3 positions(relative to the point of attachment of the phenyl group to thepiperazine ring), the groups being independently selected from halogen,C₁-C₄ alkyl, and C₁-C₄ alkoxy. Particularly preferred compounds offormula II are those where R₁-R₅ are hydrogen; A is C₄ alkylene; and Wis 8-quinolinyl, naphthyl or a phenyl group optionally up to two groupsin the 2 and/or 3 positions (relative to the point of attachment of thephenyl group to the piperazine ring), the groups being independentlyselected from chloro, methyl, and methoxy.

The present invention further encompasses compounds of Formula III:

wherein R₁, R₂, R₃, R₄, R₅, R₆, and R₇, A, and W are as defined above.

Preferred compounds of formula III are those where R₁-R₅ are hydrogen; Ais C₃-C₅ alkylene, more preferably butylene; and W is quinolinyl,naphthyl or phenyl optionally substituted with up to three groupsindependently selected from halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy,thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro,trifluoromethyl or trifluoromethoxy. Particularly preferred compoundsfor formula III are those where R₁-R₅ are hydrogen; A is C₃-C₅ alkylene,more preferably butylene; and W is 8-quinolinyl, naphthyl, or phenyl.

The invention also provides compounds of Formula IV

where

R₄ is hydrogen or C₁-C₄alkoxy;

A represents alkylene group of 2 to 6 carbon atoms;

Z is nitrogen or carbon; and

W is quinolinyl, phenyl or naphthyl, each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula IV are those where R₄ is hydrogen and Ais C₃-C₅ alkylene. More preferred compounds of formula IV are thosewhere R₄ is hydrogen; A is C₄ alkylene; Z is nitrogen; and W is8-quinolinyl, naphthyl or phenyl optionally substituted with up to twogroups in the 2 and/or 3 positions (relative to the point of attachmentof the phenyl group to the 6-membered nitrogen-containing ring), thegroups being independently selected from halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy.

The invention further provides compounds of Formula V

where

R₄ is hydrogen or C₁-C₄ alkoxy;

A represents alkylene group of 2 to 6 carbon atoms; and

W is quinolinyl, phenyl or naphthyl, each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula V are those where R₄ is C₁-C₄ alkoxy andA is C₃-C₅ alkylene. More preferred compounds of formula V are thosewhere R₄ is C₁-C₄ alkoxy; A is C₄ alkylene; and W is 8-quinolinyl,naphthyl or phenyl optionally substituted with up to two groups in the 2and/or 3 positions (relative to the point of attachment of the phenylgroup to the piperazine ring), the groups being independently selectedfrom halogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy. Particularly preferredcompounds of formula V are those where R₄ is C₁-C₄ alkoxy; A is C₄alkylene; and W is 8-quinolinyl, naphthyl, or a phenyl group substitutedin the 2 position (relative to the point of attachment of the phenylgroup to the piperazine ring) with a C₁-C₄ alkoxy, preferably methoxy,group.

The invention also provides compounds of Formula VI

where

R₄ hydrogen or C₁-C₄ alkoxy;

A represents alkylene group of 2 to 6 carbon atoms; and

W is quinolinyl, phenyl or naphthyl, each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula VI are those where R₄ is hydrogen and Ais C₄ alkylene; and W is 8-quinolinyl, naphthyl or phenyl optionallysubstituted with up to two groups in the 2 and/or 3 positions (relativeto the point of attachment of the phenyl group to the 6-memberednitrogen-containing ring), the groups being independently selected fromhalogen, C₁ -C₄ alkyl, and C₁-C₄ alkoxy.

The invention also provides compounds of Formula VI-A

where

R₄ is hydrogen or C₁-C₄ alkoxy;

A represents alkylene group of 2 to 6 carbon atoms;

Z is nitrogen or carbon; and

W is quinolinyl, phenyl or naphthyl, each of which is optionallysubstituted with up to three groups independently selected from halogen,C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino,dialkylamino, cyano, nitro, trifluoromethyl or trifluoromethoxy.

Preferred compounds of formula VI-A are those where R₄ is hydrogen and Ais C₃-C₅ alkylene. More preferred compounds of formula VI-A are thosewhere R₄ is hydrogen; A is C₄ alkylene; Z is nitrogen; and W is8-quinolinyl, naphthyl or phenyl optionally substituted with up to twogroups in the 2 and/or 3 positions (relative to the point of attachmentof the phenyl group to the 6-membered nitrogen-containing ring), thegroups being independently selected from halogen, C₁-C₄ alkyl, and C₁-C₄alkoxy.

When a compound of the invention is obtained as a mixture ofenantiomers, these enantiomers may be separated, when desired, byconventional methods such as crystallization in the presence of aresolving agent, or chromatography, for example using a chiral HPLCcolumn.

Representative compounds of the present invention, which are encompassesby Formula I, include, but are not limited to the compounds in Figure Iand their pharmaceutically acceptable salts. The present invention alsoencompasses prodrugs, e.g., acylated prodrugs, of the compounds ofFormula I. Those skilled in the art will recognize various syntheticmethodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and prodrugs of the compoundsencompassed by Formula I.

Representative compounds of the present invention, which are encompassesby Formula I, include, but are not limited to the compounds in Table 1and their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic,methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic,alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where n is 0-4, and thelike. Those skilled in the art will recognize a wide variety ofnon-toxic pharmaceutically acceptable addition salts.

The following numbering system is used to identify positions on thedibenzofuran ring portion of the compounds of the invention:

By “alkyl” and “lower alkyl” is meant straight and branched chain alkylgroups having from 1-6 carbon atoms, e.g., C₁-C₆ alkyl.

By “lower alkoxy” and “alkoxy” is meant straight and branched chainalkoxy groups having from 1-6 carbon atoms, e.g., C₁-C₆ alkoxy.

By halogen is meant fluorine, chlorine, bromine and iodine.

The amino portion of the aminoalkyl group represented by R aboveincludes groups represented by the formula Q

where W is defined above.

Th formula Q represents saturated heterocyclic ring systems such as, forexample, piperidinyl and piperazinyl, as well as unsaturatedheterocyclic ring systems such as, for example, 1, 2, 3,6-tetrahydropyrindine. Preferred Q groups are the following:

where W is defined above.

Particularly preferred W groups of the invention are (a) quinolinyl,more preferably 8-quinolinyl, (b) naphthyl, or (c) phenyl optionallysubstituted with up to two substituents independently selected fromhalogen, C₁-C₄ alkyl, and C₁-C₄ alkoxy. These optional phenylsubstituents are preferably in the 2 and/or 3 positions of the phenylgroup relative to the point of attachment of the phenyl group to the6-membered nitrogen containing ring.

Representative examples of N-aminoalkyldibenzothiophenecarboxamidesaccording to the invention are shown in Table 1 below. The number beloweach compound is its compound number. Each of these compounds may beprepared according to the general reaction Scheme I set forth below.

Compounds 1-8 in Table 1 have the following general formula A:

where R and R₅ are defined in the table.

Compounds 9-11 in Table 1 have the following general formula B:

where R and R₅ are defined in the table.

TABLE 1 Com- pound Number R₅ R 1 H

2 H

3 H

4 H

5 H

6 H

7 H

8 H

9 H

10 H

11 H

Particular compounds according to the invention include:

N-(1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride

N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(2-Methyl-3-chlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(2-Chlorophenyl)piperazin-1-yl]}butyl)-2-dibenziothiophenecarboxamidehydrochloride

N-(1-{4-[4-(2-Methylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(8-Quinolinyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]}butyl)-1-dibenzothiophenecarboxamidehydrochloride

N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-1-dibenzothiophenecarboxamidehydrochloride

N-(1-{2-[4-(1-Naphthyl)piperazin-1-yl]}ethyl)-1-dibenzothiophenecarboxamidehydrochloride

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The pharmaceuticalutility of compounds of this invention are indicated by the followingassays for dopamine receptor subtype affinity.

ASSAY FOR D₂ AND D₃ RECEPTOR BINDING ACTIVITY

Pellets of COS cells containing recombinantly produced D₂ or D₃receptors from African Green monkey were used for the assays. The sampleis homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and Ph 7.4. The sample is then centrifuged at 30,000×g and resuspendedand rehomogenzied. The sample is then centrifuged as described and thefinal tissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³H—YM 09151-2 and the compound of interest in a totalincubation of 1.0 ml. Nonspecific binding is defined as that bindingfound in the presence of 1 mM spiperone; without further additions,nonspecific binding is less than 20% of total binding. The bindingcharacteristics of representative compounds of the invention for D₂ andD₃ receptor subtypes are shown in Table 2.

TABLE 2 Compound Number¹ D₃ K_(i) (nM) D₂ K_(i) (nM) 1 3.5 285 2 5.0 242¹Compound numbers relate to compounds shown above in Table 1.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intrasternalinjection or infusion techniques. In addition, there is provided apharmaceutical formulation comprising a compound of general Formula Iand a pharmaceutically acceptable carrier. One or more compounds ofgeneral Formula I may be present in association with one or morenon-toxic pharmaceutically acceptable carriers and/or diluents and/oradjuvants and if desired other active ingredients. The pharmaceuticalcompositions containing compounds of general Formula I may be in a formsuitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glcerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropyl methycellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coolingagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be perserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservative. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe and partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water.Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa cutter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Preparation of N-aminoalkyldibenzothiophenecarboxamides

The compounds of Formula I, and the pharmaceutically acceptable acidaddition salts thereof, may be prepared according to the reactions shownbelow in Scheme 1.

wherein R₁, R₂, R₃, R₄, R₅, R₆, R₇, A, Z and W are as defined above forFormula IA.

As shown, a compound of Formula VII may be activated by1,1′-carbonyldiimidazole (CDI) or the like in solvents such astetrahydrofuran at room temperature. The resulting activated species maybe subsequently reacted with the required compound of Formula VIII toafford a compound of Formula I as the desired product.

Where they are not commercially available, the compounds of Formula VIImay be prepared by literture procedures or procedures analogous to thosedescribed in literature. The compounds of Formula VIII are either knownor capable of being prepared by various methods known in the art.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples. In some cases protection of certain reactive functionalitiesmay be necessary to achieve some of the above transformations. Ingeneral the need for such protecting groups will be apparent to thoseskilled in the art of organic synthesis as well as the conditionsnecessary to attach and remove such groups.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them. These examples illustrate thepresently preferred methods for preparing the compounds of theinvention.

EXAMPLE 1

2-Dibenzothiophenecarboxylic acid (105 mg, 0.45 mmol) and1,1′-carbonyldiimidazole (80 mg, 0.5 mmol) are stirred in 20 mLtetrahydrofuran at room temperature overnight. A solution of4-[4-(2,3-dichlorophenyl)piperazin-1-yl]-1-aminobutane (150 mg, 0.5mmol) in 5 mL of tetrahydrofuran is added. The resulting mixture isstirred for another 2 hours. The reaction mixture is then partitionedbetween dichloromethane and 10% aqueous sodium bicarbonate solution. Theorganic layer is dried (Na₂SO₄) and concentration in vacuo. Theresulting oil is subjected to preparative TLC using 10:1:0.1dichloromethane-methanol-ammonium hydroxide as eluent. This affords thetitle compound as the free base. The hydrochloride salt is prepared bytreating the free base with diethyl ether-HCl. The resultinghydrochloride salt of the title compound has a melting point of 238-240°C.

EXAMPLE 2

The following compounds of Formula 1 are prepared essentially accordingto the procedures set forth in Example 1 above.

(a)N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride (mp 225-228° C.)

(b)N-(1-{4-[4-(2-Methyl-3-chlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride (mp 230-231° C.)

(c)N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride (mp 226-228° C.)

(d)N-(1-{4-[4-(2-Chlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride (mp 226-228° C.)

(be)N-(1-{4-[4-(2-Methylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride (mp 232-235° C.)

(f)N-(1-{4-[4-(8-Quinolinyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamidehydrochloride (mp 235-238° C.)

(g)N-(1-{4-[4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl]}butyl)-2-dibenzothiophene-carboxamidehydrochloride (mp 266-268° C.)

(h)N-(1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl])butyl)-1-dibenzothiophene-carboxamidehydrochloride (mp 220-222° C.)

(i)N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-1-dibenzothiophenecarboxamidehydrochloride (mp 222-223° C.)

(j)N-(1-{2-[4-(1-Naphthyl)piperazin-1-yl]}ethyl)-1-dibenzothiophenecarboxamidehydrochloride (mp 215-218° C.)

What is claimed is:
 1. A pharmaceutical composition comprising a compound the formula:

or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, wherein R₁, R₂, R₃, R₄ are the same or different and represent hydrogen, C₁-C₆ alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O₂CR′, —NHCOR′, —COR′, —SO_(m)R′, where R′ is C₁-C₆ alkyl and m is 0, 1, or 2; or R₁, R₂, R₃, R₄ independently represent —CONR′R″, or NR′R″ where R′ and R″ independently are hydrogen or C₁-C₆ alkyl; R₅ is hydrogen or C₁-C₆ alkyl; and A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; W is phenyl, naphthyl, 1-(5,6,7,9-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quionolinyl, isoquionolinyl, benofuranyl, or benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 2. A pharmaceutical composition comprising a compound the formula:

or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, wherein R₁, R₂, R₃, R₄ are the same or different and represent hydrogen, C₁-C₆ alkyl, halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C₁-C₆ alkoxy, —O₂CR′, —NHCOR′, —COR′, —SO_(m)R′, where R′ is C₁-C₆ alkyl and m is 0, 1, or 2; or R₁, R₂, R₃, R₄ independently represent —CONR′R″, NR′R″ where R′ and R″ independent are hydrogen or C₁-C₆ alkyl; R₆ and R₇ are the same or different and represent hydrogen or C₁-C₆ alkyl; A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; W is phenyl, naphthyl, 1-(5,6,7,9-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quionolinyl, isoquionolinyl, benzofuranyl, or benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 3. A pharmaceutical composition comprising a compound the formula:

or a pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier, wherein R₁, R₂, R₃, R₄ are the same or different and represent hydrogen or C₁-C₆ alkyl; R₅ is hydrogen or methyl; and A represents an alkylene group of 2 to 6 carbon atoms optionally substituted with one or more alkyl groups having from 1 to 4 carbon atoms; W is phenyl, naphthyl, 1-(5,6,7,9-tetrahydro)naphthyl or 4-(1,2-dihydro)indenyl, pyridinyl, pyrimidyl, quionolinyl, isoquionolinyl, benzofuranyl, or benzothienyl; each of which is optionally substituted with up to three groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₄ alkoxy, thioalkoxy, hydroxy, amino, monoalkylamino, dialkylamino, cyano, nitro, trifluoromethyl and trifluoromethoxy.
 4. A composition according to claim 2, wherein the compound is N-(1-{4-[4-(2,3-Dichlorophenyl) piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(2-Methyl-3-chlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(2,3-Dimethylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(2-Chlorophenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(2-Methylphenyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(8-Quinolinyl)piperazin-1-yl]}butyl)-2-dibenzothiophenecarboxamide, N-(1-{4-[4-(2,3-Dichlorophenyl)piperazin-1-yl]}butyl)-1-dibenzothiophenecarboxamide, N-(1-{4-[4-(1-Naphthyl)piperazin-1-yl]}butyl)-1-dibenzothiophenecarboxamide, or N-(1-{2-[4-(1-Naphthyl)piperazin-1-yl]}ethyl)-1-dibenzothiophenecarboxamide hydrochloride. 